Sexual reproduction depends upon accurate chromosome segregation during meiosis. Errors in segregation lead to aneuploidy and are major causes of genetic disease and spontaneous abortion in humans. Meiosis consists of two divisions preceded by a single round of DNA replication. Meiosis I is a "reductional" division in which homologous chromosomes pair and segregate to opposite poles. Meiosis II is an equational division, similar to mitosis, in which sister chromatids segregate. The focus of this proposal is on mechanisms underlying homolog segregation. The proposed experiments utilize Drosophila male meiosis as a model system to explore how homologs pair in early meiosis and the nature of the stable bonds that ensure accurate segregation of homologs during meiosis I. Pairing of homologous chromosomes is the fundamental defining event of meiosis, yet we know almost nothing about how it occurs. We also have only a limited understanding of how chromosomes are stably connected during later stages of the reductional division to assure that exactly one member of each pair goes to each pole. The most widespread mechanism uses sister chromatid cohesion in combination with crossovers to fashion connectors called chiasmata. But many organisms such as Drosophila males don't undergo regular meiotic crossingover and so can't make chiasmata, yet accomplish error-free segregation of homologs. Our work has revealed that Drosophila males utilize special pairing sites, such as the rDNA on the X and Y chromosomes, and have two proteins (Stromalin in Meiosis (SNM) and Mod(Mdg4) in Meiosis (MNM)) that localize to those sites throughout meiosis I to stably "conjoin" the homologs. We are now in a position to make major inroads into the mechanism of conjunction. In this proposal, we will undertake experiments to address four major unsolved problems in Drosophila meiosis: 1) What is the role of homologous recombination in forming the stable connections between homologs that underlie accurate segregation. 2) What is the role of the SNM/MNM complex in mediating conjunction of homologs. 3) What is the molecular basis for homologous pairing in early prophase. 4) How are homologous pairing and conjunction related? We will use predominant genetic and cell biological methods to address these questions.